Dataset Information

Aging Impairs Mitochondrial Function and Mitophagy and Elevates Interleukin 6 Within the Cerebral Vasculature.

ABSTRACT: Background The blood-brain barrier (BBB) is critical for cerebrovascular health. Although aging impairs the integrity of the BBB, the mechanisms behind this phenomenon are not clear. As mitochondrial components activate inflammation as mitochondria become dysfunctional, we examined how aging impacts cerebrovascular mitochondrial function, mitophagy, and inflammatory signaling; and whether any alterations correlate with BBB function. Methods and Results We isolated cerebral vessels from young (2-3 months of age) and aged (18-19 months of age) mice and found that aging led to increases in the cyclin-dependent kinase inhibitor 1 senescence marker with impaired mitochondrial function, which correlated with aged mice exhibiting increased BBB leak compared with young mice. Cerebral vessels also exhibited increased expression of mitophagy proteins Parkin and Nix with aging. Using mitophagy reporter (mtKeima) mice, we found that the capacity to increase mitophagy from baseline within the cerebral vessels on rotenone treatment was reduced with aging. Aging within the cerebral vessels also led to the upregulation of the stimulator of interferon genes and increased interleukin 6 (IL-6), a cytokine that alters mitochondrial function. Importantly, exogenous IL-6 treatment of young cerebral vessels upregulated mitophagy and Parkin and impaired mitochondrial function; whereas inhibiting IL-6 in aged cerebral vessels reduced Parkin expression and increased mitochondrial function. Furthermore, treating cerebral vessels of young mice with mitochondrial N-formyl peptides upregulated IL-6, increased Parkin, and reduced Claudin-5, a tight junction protein integral to BBB integrity. Conclusions Aging alters the cerebral vasculature to impair mitochondrial function and mitophagy and increase IL-6 levels. These alterations may impair BBB integrity and potentially reduce cerebrovascular health with aging.

SUBMITTER: Tyrrell DJ

PROVIDER: S-EPMC7763766 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Aging Impairs Mitochondrial Function and Mitophagy and Elevates Interleukin 6 Within the Cerebral Vasculature.

Tyrrell Daniel J DJ Blin Muriel G MG Song Jianrui J Wood Sherri C SC Goldstein Daniel R DR

Journal of the American Heart Association 20201123 23

Background The blood-brain barrier (BBB) is critical for cerebrovascular health. Although aging impairs the integrity of the BBB, the mechanisms behind this phenomenon are not clear. As mitochondrial components activate inflammation as mitochondria become dysfunctional, we examined how aging impacts cerebrovascular mitochondrial function, mitophagy, and inflammatory signaling; and whether any alterations correlate with BBB function. Methods and Results We isolated cerebral vessels from young (2- ...[more]

PMID: 33225820

Similar Datasets

Project description:In the present study, we investigated the influence of diquat-induced oxidative stress on intestinal barrier, mitochondrial function, and the level of mitophagy in piglets. Twelve male Duroc × Landrace × Yorkshire 35-d-old pigs (weaned at 21 d of age), with an average body of 9.6 kg, were allotted to two treatments of six piglets each including the challenged group and the control group. The challenged pigs were injected with 100 mg/kg bodyweight diquat and control pigs injected with 0.9% (w/v) NaCl solution. The results showed that diquat injection decreased ADFI and ADG. Diquat decreased (P < 0.05) the activities of superoxide dismutase and glutathione peroxidase and increased (P < 0.05) the malondialdehyde concentrations. The lower (P < 0.05) transepithelial electrical resistance and higher (P < 0.05) paracellular permeability of fluorescein isothiocyanatedextran 4 kDa were found in diquat challenged piglets. Meanwhile, diquat decreased (P < 0.05) the protein abundance of claudin-1, occluding, and zonula occludens-1 in jejunum compared with the control group. Diquat-induced mitochondrial dysfunction, as demonstrated by increased (P < 0.05) reactive oxygen species production and decreased (P < 0.05) membrane potential of intestinal mitochondria. Diquat-injected pigs revealed a decrease (P < 0.05) of mRNA abundance of genes related to mitochondrial biogenesis and functions, PPARg coactivator-1α, mammalian-silencing information regulator-1, nuclear respiratory factor-1, mt transcription factor A, mt single-strand DNA-binding protein, mt polymerase r, glucokinase, citrate synthase, ATP synthase, and cytochrome coxidase subunit I and V in the jejunum. Diquat induced an increase (P < 0.05) in expression of mitophagy-related proteins, phosphatase and tensin homologue deleted on chromosome 10-induced putative kinase, and Parkin in the intestinal mitochondria, as well as an enhancement of the ratio of light chain 3-II (LC3-II) to LC3-I content in the jejunal mucosa. These results suggest that oxidative stress disrupted the intestinal barrier, caused mitochondrial dysfunction, and triggered mitophagy.

Project description:In the present study, we investigated the influence of weaning on antioxidant status, intestinal integrity, mitochondrial function, and the mitophagy level in piglets (weaned at 21 d) during the 1 wk after weaning. The redox status was measured by antioxidant enzymes activities, related genes expression, and malondialdehyde (MDA) content in jejunum. The intestinal barrier function was assessed by the Ussing chamber and expression of tight junction proteins in the jejunum. The function of intestine mitochondria was measured by mitochondrial DNA (mtDNA) content and activities of mitochondria oxidative phosphorylation complexes. The levels of light chain 3-1 (LC3-I), light chain 3-II (LC3-II), PTEN-induced putative kinase 1 (PINK1), and Parkin were determined to investigate whether mitophagy is involved in the weaning process. The results showed that, as compared with the preweaning phase (d 0), weaning suppressed (P < 0.05) the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) on d 3 and d 7 postweaning, decreased (P < 0.05) the expression of copper and zinc superoxide dismutase (Cu/Zn-SOD), manganese-containing superoxide dismutase (Mn-SOD) on d 3 postweaning, declined (P < 0.05) the level of glutathione peroxidase 1 (GPX-1) and glutathione peroxidase 4 (GPX-4) on d 3 and d 7 postweaning, and increased (P < 0.05) MDA content in jejunum on d 3 and d 7 postweaning. The jejunal transepithelial electrical resistance and levels of occludin, claudin-1, and zonula occludens-1 on d 3 and d 7 postweaning were reduced (P < 0.05), and paracellular flux of fluorescein isothiocyanatedextran (4 kDa) on d 3 and d 7 postweaning was increased (P < 0.05). Weaning induced mitochondrial dysfunction, as demonstrated by decreased (P < 0.05) content of mtDNA on d 3 and d 7 postweaning and declined (P < 0.05) activities of mitochondria complexes (I, II, III, IV) in jejunum on d 1, d 3, and d 7 postweaning. Weaning led to an increased (P < 0.05) expression level of mitophagy-related proteins, PINK1 and Parkin, in the intestinal mitochondria, as well as an enhancement (P < 0.05) of the ratio of LC3-II to LC3-I content in the jejunal mucosa on d 1, d 3, and d 7 postweaning. These results suggest that weaning disrupted intestinal oxidative balance, and this imbalance may impair intestinal barrier and mitochondrial function and trigger mitophagy in piglets.

Dataset Information

Aging Impairs Mitochondrial Function and Mitophagy and Elevates Interleukin 6 Within the Cerebral Vasculature.

Publications

Aging Impairs Mitochondrial Function and Mitophagy and Elevates Interleukin 6 Within the Cerebral Vasculature.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets